The earliest European exploration near Seqyoyah NWR was De Soto's 1541 visit to a location along the Arkansas River in what is now western Arkansas. The earliest Europeans to visit the area around Sequoyah NWR were probalby French traders who bargained with the natives, bringing glass beads, metal containers, and weapons, including knives and guns, in exchange for commodities such as bison hides, meat, and tallow that were shipped down the Arkansas River. Through the 1600s and 1700s, representatives of the Spanish and French governements competed for trade with native groups between the Mississippi River and New Mexico.

In 1803, the Louisana Purchase brought this area under the control of the United States government. Non-Native Americans almost immediately began to settle in and around the area. The government had another plan for this area - to use it as a refuge for native groups whose traditional territories were coveted by Euroamerican settlers. Beginning in 1809, tribes from the southeastern United States began moving west of the Mississippi River. The part of Seqyouah NWR north of the Arkansas or Canadian rivers became part of the Cherokee Nation, while the portion south of both rivers was part of the Choctaw Nation. The tribes governed themselves, but they had no control or jurisdiction over the numerous Euroamerican trespassers who continued to pour into Indian Territory.

During the Civil War, both the Cherokee and Choctaw governments sided with the South, but many families were Union sympathizers. No matter which side won the war, all the residents in Indian Territory were losers due to destruction of property, lives, and mechanisms of social stability (schools, churches, law enforcement, etc.). The federal government imposed new conditions on the tribes, including the requirement that freed slaves be adopted into the tribes as citizens and granting of easements for railroad construction (a move that brought even more non-Native Americans into the Territory). By the 1890 census, there were more non-Indians than Indians in both the Cherokee and Choctaw nations.